HCA

In aging and many disease states, the energy
production capacity of the body’s cells is diminished.
The mitochondria are the structures within the cell
responsible for generating energy from oxygen and
nutrients. If their number is reduced or their function
is impaired, free radicals are produced and damaging toxins
accumulate in the cells. These toxins further damage the
mitochondria and impair other aspects of cellular function.
Many of the most common health problems, such as obesity,
diabetes, and many problems associated with aging, arise
from problems in cellular energy production. As one group of
researchers has put this, "[a]ging is associated with an overall
loss of function at the level of the whole organism that has
origins in cellular deterioration. Most cellular components,
including mitochondria, require continuous recycling
and regeneration throughout the lifespan."1 Another has
observed, "[m]itochondrial biogenesis [the creation of new
mitochondria] is a key physiological process that is required
for normal growth and development and for maintenance
of ongoing cellular energy requirements during aging."2
These observations link two key aspects of mitochondrial
health, preventing and removing damaged mitochondria
(mitophagy) and creating new mitochondria (mitogenesis).

Although the importance of the mitochondria as a
central point of health has been accepted for decades, over
the last few years the understanding of the mechanisms
involved has changed significantly. Twenty or ten years ago,
antioxidants and the free radical theory of aging largely
dominated thinking. Today, the importance of mitochondrial
biology linking basic aspects of aging and the pathogenesis
of age-related diseases remains strong, yet the emphasis has
changed. The focus has moved to mitochondrial biogenesis
and turnover, energy sensing, apoptosis, senescence, and
calcium dynamics.3

What Promotes Mitochondrial Biogenesis?
The body maintains a complex network of sensors and
signaling functions to maintain stability despite a constantly
changing environment and numerous challenges. Of special
note is the concept of hormesis, meaning a state in which
mild stress leads to compensation that improves the ability
of the body to respond in the future to similar challenges. It
turns out that many of the approaches that are associated
with longevity and healthy aging promote hormesis. In terms of mitochondria biogenesis, these include caloric restriction,
certain nutrient restrictions or shortages, caloric restriction
mimetics, and exercise.

Many of the mechanisms that activate mitochondrial
biogenesis in the face of hormesis have been elucidated.
Keeping in mind that there always must be a balance between
the elimination of worn-out and defective mitochondria and
the generation of new ones, the activators of both actions can
overlap. For instance, low energy levels (caloric restriction)
and increased reactive oxygen species/free radicals can
promote the activity of special cellular control points. These
include activating metabolic sensors such as AMP kinase/
AMPK (adenosine monophosphate kinase) and the protein
known as SIRT1 (sirtuin 1, i.e., silent mating type information
regulation 2 homolog 1). Activated AMPK is an indicator that
cellular energy is low and serves as a trigger to increase
energy production. It inhibits insulin/IGF-1/mTOR signaling,
all of which are anabolic and can lead not just to tissue
production, such as muscle growth, but also to fat storage.
Along with SIRT1, AMPK activates the biogenesis of new
mitochondria to enable the cell to generate more energy. At
the same time, activated AMPK and SIRT1 increase the activity
of a tumor suppressor that induces mitophagy. The balance
of the dual activations replaces defective mitochondria with
newly formed functionally competent mitochondria.

A key to health and healthy aging is to regulate the
catabolic processes via controlled amounts and
types of stressors such that worn out mitochondria
are removed without overshooting the mark and reducing
overall cellular and tissue functionality. The most successful
way to maintain this balance is to follow the body’s own
natural metabolic signals rather than to attempt to override
the body’s checkpoints. AMPK and SIRT1 ultimately are
energy/nutrient sensors or control points. Hence rather than
attempting to manipulate these directly, it likely is safer and
ultimately more effective to address the factors in the cell
that these sensors sense. The recent attention in the issue of
aging to the role of NAD+ (the oxidized form of nicotinamide
adenine dinucleotide) is a good example of this principle.
Directions coming from the nucleus of the cell that help
to regulate the normal production of NAD+ and the ratio
between distinct pools found in the cytoplasm and in the
mitochondria decline with age. The changes in the NAD+
from the nucleus lead to a disruption on the mitochondrial
side. In terms of energy production, it is a bit like losing a link
or two in the timing chain on your car engine with a resultant
reduction in engine efficiency. To date, attempts to increase
NAD+ in cells via supplementation with precursors have
not proven particularly successful. Major benefits have been
demonstrated in animal models only in the already seriously
metabolically impaired or the relatively old. Recent research
on oral supplementation has led to at least one extremely
difficult article which, at least in this author’s opinion, delivers
more smoke than heat.4,5 There is, however, an argument to
the effect that supplementing together both nicotinamide
riboside (a NAD+ precursor) and a sirtuin activator, such as
pterostilbene, may prove to be more successful.

It turns out that there are key points in normal cellular
energy generation processes that strongly influence the
NAD+ pools available for the cell to draw upon and the rate at
which NAD+ can be replaced in these pools. Aging has been
shown to promote the decline of nuclear and mitochondrial
NAD+ levels and to increase the risk of cancer along with
components of the metabolic syndrome. It is significant
that the risks of these conditions can be reduced in tandem.
Three places to start are 1) the pyruvate dehydrogenase
complex, 2) the tricarboxylic acid cycle (TCA cycle) also
known as the Krebs Cycle, and 3) the malate shuttle. A fourth
junction is Complex I of the electron transport system, again,
in the mitochondria.6 Manipulation of steps (1) and (2)
already is being used in cancer treatment.7 Readily available
dietary supplements can influence all four of these metabolic
bottlenecks.

Supplements for Promoting Mitochondrial Biogenesis
Medicine has started to pay a great deal of attention to
effecting mitochondrial biogenesis through not just drugs,
but also dietary supplements. Those interested should
go online and look up "Mitochondrial Biogenesis:
Pharmacological Approaches" in Current Pharmaceutical
Design, 2014, Vol. 20, No. 35. Quite a few options are
mentioned, including well known compounds, such as
R-lipoic acid (including with L-carnitine), quercetin and
resveratrol, along with still obscure supplements, including
various triterpenoids and the Indian herb Bacopa monnieri.

Pomegranate, French White Oak and Walnuts
The pomegranate, with its distinctive scarlet rind (pericarp)
and vibrantly colored seed cases (arils), is one of the oldest
cultivated fruits in the world. This exotic fruit features
prominently in religious texts and mythological tales and has
been revered through the ages for its medicinal properties.
An image of a pomegranate even can be found on the shield
of the British Royal College of Medicine. Numerous studies
have demonstrated the benefits of the fruit for cardiovascular
health with other benefits suggested in areas ranging from
arthritis to stability of cell replication to bone health. Now a
study in Nature Medicine (July 2016) has uncovered perhaps
the most important benefit of all, the ability of pomegranate
compounds (ellagitannins) transformed by gut bacteria to
protect the mitochondria of the muscles and perhaps other
tissues against the ravages of aging. The mitochondria are
the energy generators of the cells and the weakening of
this energy generating function in an increasing percentage
of mitochondria as we age is a primary source of physical
decline over the years. Urolithin A, a byproduct of gut
bacterial action on pomegranate compounds, allows the
body to recycle defective mitochondria and thereby slow or
even reverse for a time some of the major aspects of aging.
The lifespan in a nematode model of aging was increased by
more than 45 percent. Older mice in a rodent model of aging
exhibited 42 percent better exercise endurance. Younger
mice also realized several significant benefits.8

Beginning almost three decades ago, there were
numerous speculations in the research world regarding the
so-called "French Paradox" in which the French consumed
quite large amounts of saturated fat in the form of butter and cheese, yet consistently experienced much lower
rates of cardiovascular disease than did Americans. Not
only that, the French, especially in the southwest of the
country, typically led longer lives even in the areas noted for
consuming large amounts of goose fat and pate de foie gras,
which is to say, not just the Mediterranean diet based on
olive oil, etc. One hypothesis put forth very early on was that
it was the French consumption of red wine that protected
them. It was thought that red wine components, including
anthocyanidins, proanthocyanidins and resveratrol, are the
protective compounds. Not considered until recently is that
French red wines traditionally have been aged in casks made
from white oak (Quercus robur). White oak contains roburin
A, a dimeric ellagitannin related chemically to punicalagin.
Human data show relatively good absorption and conversion
of roburins into substances including urolithin A and ellagic
acid—as compared with ellagitannins in general, which
evidence only poor absorption. Hence, the benefits of good
red wine traditionally produced and good cognac (also aged
in oak barrels) involve urolithin A. Notably, the benefits of
roburins, most likely derived from the conversion to urolithin
A, go beyond mitophagy to include ribosomes, referring to cell
components that translate DNA instructions into specific
cellular proteins.9,10,11,12

Other sources of ellagitannins have been shown to lead
to the production of urolithin A by bacteria in the human
gut. Not surprisingly, sources of ellagitannins are foods
long associated with good health longevity, including not
just pomegranate and oak-aged red wine, but also walnuts
(and a smattering of other nuts), strawberries, raspberries,
blackberries, cloudberries and even black tea in small
amounts.

Exercise and Pyrroloquinoline Quinone (PQQ)
Peroxisome proliferator-activated receptor gamma coactivator
(PGC-1á) is the master regulator of mitochondrial
biogenesis.13 Exercise is perhaps the most significant
activator of PGC-1á that most individuals can access.
Exercise, furthermore promotes mitochondrial biogenesis
through a number of other pathways, especially endurance
and interval training.14

There are non-exercise options. You can’t take PGC-1á
orally because it is a large protein molecule which does not
survive digestion. PQQ is a small molecule that is available
when ingested and that increases circulating PGC-1á. PQQ
supplementation leads to more mitochondria and more
functional mitochondria.15

Fasting, Ketogenic Diets and Fasting-Mimicking Supplements
As already discussed, fasting promotes mitochondrial
biogenesis by AMPK activation.16 AMPK senses the energy
status of the cell and responds both to acute shortages,
such as that induced by exercise, and to chronic shortages,
such as from fasting. Probably due to an overall reduction
in metabolic rate, chronic caloric restriction (as opposed to
intermittent fasting) contributes to the health of mitochondria
rather than biogenesis.17 The robustness of AMPK response
decreases with age.18

Ketogenic diets (very low carbohydrate diets) also
promote increases in mitochondria.19 Few individuals are
willing or able to follow ketogenic diets chronically just as
few individuals are willing to undergo routine fasts. Fasting-mimicking
supplements offer an alternative approach. The
dietary supplement (-)–hydroxycitric acid (HCA) is the best
researched of these compounds. (Keep in mind that there
is a vast difference in the efficacy of commercially available
forms.20) Researchers have proposed that HCA used properly
can activate mitochondrial uncoupling proteins and related
effects.21

Furthermore, according to a study published in the journal
Free Radical Research in 2014, HCA improves antioxidant status
and mitochondrial function plus reduces inflammation in fat
cells.22 Inflammation is linked to the metabolic syndrome at
the cellular level by way of damage to the antioxidant enzyme
system (e.g., superoxide dismutase, glutathione peroxidase,
glutathione reductase) and mitochondria. This damage, in
turn, propagates further production of pro-inflammatory
mediators (e.g., TNF-á, MCP-1, IFN-ã, IL-10, IL-6, IL-1â).
HCA protected fat cells from ER stress by improving the
antioxidant status to reduce oxidative stress (i.e., reduce
ROS) and improve the function of the mitochondria to
short circuit an ER stress—inflammation loop in these cells.
Reducing TNF-á is important in that doing so removes a
major impediment to mitochondrial biogenesis.23

Other Supplements to Promote Mitochondrial Biogenesis

Scholarly reviews looking at natural compounds such as
those that are found in anti-aging diets suggest yet other
supplements to promote mitobiogenesis. For instance,
it turns out that hydroxytyrosol, the most potent and
abundant antioxidant polyphenol in olives and virgin olive
oil, is a potent activator of AMPK and an effective nutrient
for stimulating mitochondrial biogenesis and function via
what is known as the PGC-1á pathway.24 Another herb with anti-aging effect, this time by activating the malate shuttle
mechanism mentioned above, is rock lotus (Shi Lian Hua).
This herb has been described in detail in this magazine in
the article, "Uncovering the Longevity Secrets of the ROCK LOTUS."25

Conclusion
It is possible to improve the functional capacity of the
mitochondria through dietary practices, exercise and
supplements. Indeed, a number of compounds have been
identified by researchers as mitochondrial nutrients. These
compounds work together to increase the efficiency of energy
production, to reduce the generation of free radicals, and so
forth and so on. Likewise, these nutrients have been shown
to improve the age-associated decline of memory, improve
mitochondrial structure and function, inhibit the ageassociated
increase of oxidative damage, elevate the levels
of antioxidants, and restore the activity of key enzymes.
Perhaps best of all, the body can be encouraged both to
remove damaged mitochondria (mitophagy) and to create
new ones, which is to say, mitochondrial biogenesis.

Two years ago in this space the topic was the
entourage effect and how it differed from nutritional
and medical findings involving synergy: "Whereas
synergism involves components each of which is active on its
own and which in combination yield effects greater than the
sum of the individual contributions, the entourage effect may
involve components most of which on their own may exhibit
little or no benefit or may yield benefits that are otherwise
unrelated."1 In practice, of course, there is more than a
little overlap and one finds this all the time with foods and
supplements. A good example is the so-called French paradox,
generally presented as the supposed paradox between the
French consumption of comparatively large percentage of
calories as fat, especially as animal fat, and the Gallic low rate
of heart disease.

Is the French Paradox Explained by Nutrient Synergies?
Sardonic observers sometimes remark that Americans
count calories with neat little categories for carbohydrates,
fat and protein whereas the French are only concerned with
how food tastes and how the meal looks, its "presentation."
Assuming that the consumption of animal fat matters, a point
increasingly in question, the French classically have not cared
while enjoying enviable levels of health, hence, by Anglo-
American lights, the paradox. The traditional French diet is >42
percent fat, much of it either saturated or monounsaturated.
The French (traditionally, at least, maybe still) drink red wine
daily, yet outlive Americans (81.6 years versus 78.8 years, as
of 2015, other statistical bases giving similar results).2 The
French also suffer from fewer cases of coronary heart disease
and, in actuality, remain ambulatory and self-sufficient much
longer than do Americans, meaning that statistics of relative
life expectancy should be balanced by a close look at morbidity
statistics. According to the 2014 World Health Organization
data set, the French rank second in the world, behind South
Korea, for having the lowest mortality rates from coronary
heart disease. America? We rank 44th.3 Significantly, in France
they consume almost no sugary drinks and eat very little sugar
in any form. These dietary practices should be contrasted with
those in the States.4

A new report from the USDA says Americans are eating
less fat than we did 30 years ago. Here's the opening from
an online article about the report:5
On average, Americans are eating 10g less fat per day
today than they were in the late 1970s, according to
new research. In a report comparing food consumption
patterns in 1977–78 versus 2005–2008, Biing-Hwan Lin
and Joanne Guthrie from USDA's Economic Research
Service found that on average, Americans consumed
75.2g of fat in 2005–08 compared with 85.6g in 1977–78.
Meanwhile, the percentage of total calories derived
from fat also declined substantially from 39.7% to 33.4%
between 1977 and 2008, said the authors.

Of course, there is no paradox if the long-standing
condemnation of the role of fat and saturated fats in
cardiovascular disease is mistaken, as discussed in last
month's column and previously in Heart Matters Do Statin Drugs. However, let's assume that there is a connection and
that the paradox, as often suggested, is a result of the French
love of red wine. Is wine's protection from a single magic
phytonutrient, resveratrol, or is the combination of ingredients
the key?

Many who argue that there is a paradox suggest that
the phytochemical known as resveratrol is responsible for
the low rates of cardiovascular disease. Critics argue that
this is nonsense because there simply is not enough of the
compound present to exert any effect. In fact, just this point
was the focus of an exchange back in 2008 in which a colleague,
Joseph Evans, and I were participants.6 Subsequent findings
decisively have proven that Evans and I were correct and our
interlocutor mistaken in both his evidence and his arguments.

The skeptic's argument went like this: "The potency of
most of the nutritional supplements labeled as resveratrol
is in the range of 30 mg to 100 mg. This is 30 to 100 times
lower than doses thought to be in the range for therapeutic
effects in humans." Our response was that red wine is a widely
studied source of the combination of resveratrol and quercetin
and that significant health benefits are associated with men it was demonstrated that "the platelet antiaggregatory effect
of de-alcoholized red wines could be computed...from its
concentrations of resveratrol and quercetin."7 Similarly, the
combination of resveratrol and quercetin exerts a powerful
synergy in the inhibition of inducible nitric oxide (the form
linked to inflammation).8 In animals fed a high-cholesterol
diet, the human equivalent of 210 mg resveratrol per day
improved endothelial function.9 However, more was not
better, with animal experiments demonstrating that, in human
equivalent amounts, approximately 360 mg per day led to
greater life expectancy than approximately 1,565 mg per day.10
Finally, there is experimental evidence that the combination
of nutrients such as pterostilbene, quercetin, and resveratrol
might be more active than any one of these alone at much
higher dosages with research showing that subeffective doses
of combinations of anti-inflammatory compounds can inhibit,
for instance, carcinogenesis.11

In contention was whether relatively modest amounts
of resveratrol in combination yield significant health benefits
for humans despite the amounts being ineffective on their
own. A recent clinical study provides an instance of proof
that is in line with other studies published since 2008.12 In
a randomized, placebo-controlled crossover clinical trial
with 29 overweight and obese subjects, trans-resveratrol and
hesperetin taken together were effective in altering a marker
related to insulin resistance and improving metabolic and
vascular health. (Hesperetin is a flavanone, a particular type of
flavonoid.) Treatment was one capsule daily for eight weeks and
a washout period of six weeks with 90 mg resveratrol and 120
mg hesperetin and placebo. Neither resveratrol nor hesperetin
was efficacious by itself, whereas together they significantly
decreased fasting and postprandial plasma glucose, increased
the oral glucose insulin sensitivity index and improved arterial
dilatation.13 In other words, combining these nutrients is
pivotal in promoting their benefits.

Underappreciated Nutrient Combinations

Magnesium and Potassium
Not usually considered as an aspect of the French diet that
separates it from American nutrient intake is the ingestion
of minerals important for blood pressure and blood sugar
regulation, such as magnesium and potassium. Americans
notoriously do not consume green vegetables, primary dietary
sources of both minerals. This is a shame because dietary
potassium regulates vascular calcification and arterial stiffness,
which is to say, two major factors determining cardiovascular
health.14 There is much noise made about lowering sodium
intake, but it is the ratio of sodium to potassium in the diet
that determines blood pressure, not the simple amount of
sodium.15

The combination of magnesium and potassium arguably
is particularly efficacious for a number of reasons. For one, the
development of insulin resistance impedes the proper uptake
of potassium.16 Magnesium deficiency inclines subjects
toward insulin resistance. There is considerable evidence that
inadequate magnesium predisposes individuals to potassium
deficiency and makes this deficiency difficult to treat with
potassium alone. Magnesium, which is a natural calcium
channel blocker, controls the flow of sodium and potassium
across the cell membrane and therefore potentiates cellular
replenishment of potassium.17 Significantly, Mildred Seelig,
the great magnesium researcher, pioneered an approach in
which the ingestion of a potassium and magnesium salt with
fixed ratios of the two minerals and a certain minimum per
day proved to be adequate to reverse and control moderate
hypertension.18,19

Improvement in bone health is another benefit that
long-time readers of these TotalHealth articles may recall is
associated with an adequate consumption of magnesium
and potassium. In older individuals an increased intake of
animal protein (but not plant) in conjunction with a significant
intake of green vegetables, i.e., sources of magnesium and
potassium, is associated with better bone health.

How About Food/Nutrient Combinations?
Some quite simple food combinations easily improve nutrient
uptake. For instance, today there is much hype about the
development of "golden rice" via genetic modification as
a means of overcoming vitamin A deficiencies in poorer
regions of the world. Not mentioned in this hype is that these
areas are so poor that they have no fats or oils available with
which to cook food and that the mere cooking of vegetables
in oil largely resolves the vitamin A issue. In fact, the same
approach is true for improved nutrient bioavailability in
developed countries. In one trial, merely adding soybean oil
in salad dressing improved carotenoid and fat-soluble vitamin
bioavailability in salad vegetables.20 Similarly, co-consuming
cooked whole eggs is an effective way to enhance carotenoid
absorption from other carotenoid-rich foods, such as a raw
mixed-vegetable salad.21

A word of caution on oils: Recent research strongly
suggests that olive oil and coconut oil are preferable to soybean
oil. "Rich in unsaturated fats, especially linoleic acid, soybean
oil is assumed to be healthy, and yet it induces obesity, diabetes,
insulin resistance, and fatty liver in mice."22,23 Moreover, in
general the US diet exhibits an excessive and unhealthful
ratio of omega-6 to omega-3 fatty acids.24 Butter, by the way,
after years of condemnation, appears to be neutral as a fat for
most purposes. A recent systematic review and meta-analysis
suggests relatively small or neutral overall associations of
butter with mortality, CVD, and diabetes.25,26 Any worries would
appear to be easily overcome by simply eating more leafy green
vegetables to increase daily magnesium intake!27

HCA and a Largely Unknown Positive Combination
One of the more interesting compounds available in the
American health food market, albeit of highly variable
and often suspect quality, is (–)-hydroxycitric acid (HCA,
always sold as a salt) (extracted from Garcinia cambogia, G.
atroviridis, G. indica and other G. species).28 Medically, HCA
has been shown to exhibit potential additive effects of with,
for instance, atorvastatin treated hyperlipidemic patients.29
Almost never pointed out by the marketers of HCA is that the
compound's mechanism of action is inhibited by diets that are
very high in fats and/or alcohol just as the mechanism is not
operational under fasting conditions. Just as an inadequate level of intake or the intake of poor quality salts leads to a
failure to achieve benefits, so does intake under improper
conditions.30,31,32 One approach to preserving benefits even
in the face of high fat and/or high alcohol intake is to ingest
HCA along with the phytonutrient known as caffeic acid.
Caffeic acid is found in quite small amounts in some, but not
all green coffee bean extracts; it should not be confused with
chlorgenic or caffeoquinic acids.33,34 Effectively using HCA with
a coffee extract to reduce the reverse effects of fat and alcohol
is patented.35

Two Bad Combinations Typical of the American Diet
Just as there are "good" nutrient combinations, such as
examined above, there are "bad" nutrient combinations.
Sugars and refined carbohydrates increase the absorption
of fats from meals while reducing the oxidation of fats for
energy. The evidence against coupling refined carbohydrates
and fats is clear and unambiguous. Similarly, there is an
unfortunate interplay between the consumption of sugars/
refined carbohydrates and table salt leading to impaired blood
pressure regulation.36

Low glycemic index diets improve glycemic (blood sugar) response and variability as well as promote the metabolism of fat for energy; they may promote long-term health.37,38

Taken in a milkshake, fructose (30 g) increased postprandial lipemia by 37 percent compared with control; glucose (17.5 g) increased postprandial lipemia by 59 percent.39 (Lipemia is the presence in the blood of an abnormally high concentration of emulsified fat, meaning primarily triglycerides, not cholesterol.)

In Syndrome X/insulin resistant subjects (BMI of 30), glucose consumption (50 g) led to a 15.9 percent greater glycemic response and a 30.9 percent greater insulin response than did fructose (50 g). This is true in part because fructose is processed in the liver and then released later as glucose and/or converted into fat.

On an energy balanced diet in these same subjects, fructose compared with glucose increased carbohydrate oxidation 31 percent, but decreased fat oxidation by 39 percent.40

Conclusion
The benefits of foods and the nutrients that they supply, as
also is true of supplements, is highly dependent on food
and nutrient combinations. Many nutrients that clinically
are inactive on their own, including even at large levels
of intake, are beneficial when consumed with appropriate
partners. Resveratrol, so often associated with red wine and
the French paradox, is but one example of this phenomenon.
Many other everyday combinations, such as magnesium and
potassium, similarly exhibit positive dose relations. Contrarily,
certain combinations are not good if habitually practiced. The
combination of sugars/refined carbohydrates with fats, such
as the far too widely consumed omega-6 fatty acids found in,
for instance, soybean oil, is one example of a pairing that, if
consumed regularly, tends to impair aspects of metabolism,
including the oxidation of fats for energy. Likewise,
consumption patterns that couple sugars with salt can lead to
health consequences, such as blood pressure dysregulation,
not typical of either nutrient consumed by itself.

"Supplements Target Ketogenesis and Metabolic Flexibility
for Sports and Health."1 (June 2016) Last month there was
a review of the state of caloric restriction / fasting and
ketogenic diets today. However, many readers have little
interest in either caloric restriction or ketogenic diets as
lifestyle choices. Both of these approaches are difficult to
follow even if being utilized for specific health purposes.
Nevertheless, their basic principles have application to
general health and to athletics. The foremost impediment
to taking advantage of these approaches was laid out in the
2016 article.

A major problem in achieving keto-adaptation by
diet alone is that most individuals who have been
raised on Western-style diets can take six months
or more to make the shift and this shift becomes
ever more difficult as we age. Studies examining
the role of carbohydrates in the metabolism
with roughly 30 year old males in good physical
condition have revealed, for instance, that even
transitioning from a high glycemic index diet to a
low glycemic index diet while maintaining the same
ratio of carbohydrate, fat and protein can take more
than four weeks. Shifting to fatty acid metabolism
for energy can be difficult.

For most of us, the issue is whether a moderate change in
diet accompanied by a judicious utilization of special foods
and dietary supplements can achieve the goals usually
associated with caloric restriction, fasting and ketogenic
diets. Fortunately, the answer for the preponderance of
readers is "yes." Both for anti-aging purposes and for
athletics, metabolic flexibility likely can be achieved through
approaches within the reach of almost everyone. The goal is
not to be ketogenic all the time, but to be able to metabolize
ketones and free fatty acids routinely and easily. For a nice
introduction to the distinction, readers might visit the blog
entitled "Ketogenesis, Measuring Ketones, and Burning Fat
vs Being in Ketosis."2

The Diet

Previously in these pages, it was noted that consuming
too little protein presents issues, but, likewise, too much
protein in the diet, meaning above roughly 30 percent of
calories, defeats a major goal of caloric restriction, which
is to not just reduce circulating insulin, but also to avoid
elevating insulin-like growth factor-1 (IGF-1). Although
those not trained in nutrition seldom realize this, protein
sources can be used for gluconeogenesis, which is to say, to
produce glucose from, non-carbohydrate sources. It is not
just consuming too little fat and too much carbohydrate or
too much of these two together with too little protein that
defeat the aims of an anti-aging diet.

The recent Prospective Urban Rural Epidemiology
(PURE) study followed 135,335 adults in eighteen countries
for over seven years with respect to morbidity and mortality
in terms of cardiovascular disease, strokes and non-cardiovascular
disease mortality as correlated with the
effects of nutrients.3 In an interview, Dr. Mashid Dehghan,
the lead author, reported that Participants were categorized into quintiles of
nutrient intake (carbohydrate, fats, and protein)
based on percentage of energy provided by
nutrients. We assessed the associations between
consumption of carbohydrate, total fat, and each
type of fat with cardiovascular disease and total
mortality.

As noted by the researchers, their results flatly contradict
decades of nutritional advice:
High carbohydrate intake was associated with
higher risk of total mortality, whereas total fat
and individual types of fat were related to lower
total mortality. Total fat and types of fat were not
associated with cardiovascular disease, myocardial
infarction, or cardiovascular disease mortality,
whereas saturated fat had an inverse association
with stroke. Global dietary guidelines should be
reconsidered in light of these findings.

In the PURE study, those who consumed at least 35 percent
of their calories from fat were 23 percent less likely to die
than those who consumed only 10 percent or less as fat.
According to PURE findings, the higher the fat intake,
the less the chance of stroke. Those who consumed 77
percent of their calories as carbohydrates were 28 percent
more likely to die than those who consumed less than 46
percent as carbohydrates. The conclusion of the study? "In
a nutshell, a healthy diet based on the PURE results would
be rich in fruits, beans, seeds, vegetables, and fats, include
dollops of whole grains, and be low in refined carbohydrates
and sugars."

The observant reader who takes the time to look at
the PURE study's findings will quickly realize that the traditional reliance on "markers" such as blood LDL-cholesterol levels—markers long used to argue against the inclusion saturated fats any large amount of fats in general
in the diet as well to promote carbohydrate consumption—
does not correspond well with the actual endpoints of
morbidity and mortality. This does not mean that the PURE
diet needs to be ketogenic. To quote from the TotalHealth
2016 article, As admitted by Ben Greenfield, a serious triathlete
who was tested with regard to the ergogenic benefits
of a ketogenic diet, "after the study at University of
Connecticut, I personally quit messing around with
ketosis and returned to what I considered to be a
more sane macronutrient intake of 50-60% fat, 20-
30% protein, 10-30% carbohydrate."4

As a practical matter, a more normal diet with supplements
might look like this:
The diet should not be high in simple sugars,
fructose or refined carbohydrates. For non-athletes
and those looking primarily to increase
metabolic flexibility, the diet should resemble a
modified Sears Diet, meaning approximately 20 -
30 percent protein, 30 - 40 percent carbohydrate
and 30 - 40 percent fat. For athletes and individuals
who seriously want to initiate and maintain a fat-adapted
diet, Ben Greenfield's suggestion is more
in order: "50-60% fat, 20-30% protein, 10-30%
carbohydrate."

Those who want to achieve most of the benefits of a
ketogenic diet without undergoing the grueling restrictions
normally involved (limitations not just on carbohydrate
intake, which are extreme, but also on protein intake) should
consider the fact that ketone bodies supply 2–6 percent of
the body's energy requirements after an overnight fast (no
eating at bedtime) with the higher figure reflecting a longer
period without eating. After three days of fasting, 30–40
percent of energy needs are met by endogenously produced
ketones. Such facts, again, lead to at least two possibilities
aside from caloric restricted and ketogenic diets. First, will
consuming exogenous ketones as esters or salts provide
the same benefits as special diets? Second, is there a role
for dietary supplements in delivering these benefits?

Ketones (Acetoacetate and β-hydroxybutyrate)
Esters and Salts?

The new kid on the block in anti-aging and sports
supplements is oral ketones, including a ketone ester
(D-beta-hydroxybutyrate and D 1,3-butanediol) sports drink
and ketone salts, typically beta-hydroxybutyrate bound to
calcium, magnesium, potassium or sodium. A limited body
of research indicates that such supplements may improve
very long-duration endurance performance, but relatively
little is known about their impact on short-duration
and high-intensity workouts. Likewise, it is unclear that
supplementation with ketones delivers the same benefits
as adaptation to a ketogenic diet.

As one can learn from a variety of sources, "ketone
bodies are three water-soluble molecules that are produced
by the liver from fatty acids during periods of low food
intake (fasting), carbohydrate restrictive diets, starvation
and prolonged intense exercise… These ketone bodies are
readily picked up by the extra-hepatic [outside the liver]
tissues, and converted into acetyl-CoA which then enters
the citric acid cycle and is oxidized in the mitochondria for
energy. In the brain, ketone bodies are also used to make
acetyl-CoA into long-chain fatty acids."5

In the liver, metabolism of fatty acids for energy, as
opposed to ketone bodies, works in conjunction with a
normal pattern of activity in the mitochondria, including
the citric acid cycle. Ketone bodies are formed when there
is not enough glucose from either carbohydrates, including
glycogen, or the breakdown of protein to fuel the cycle.
Technically, the supply of oxaloacetate is exhausted, at
which point the liver produces and exports ketone bodies
to tissues that can metabolize ketones fully. In starvation
and under very low carbohydrate intake accompanied by
restrained protein intake, ketone bodies supply up to 50
percent of the energy requirements for most body tissues
and up to 70 percent of the energy required by the brain.
The blog mentioned above provides a nice diagram of the
cellular steps involved in ketone formation. The author also
helpfully points out:

As I have written about eight hundred times in
other posts, you do not need to be generating high
levels of ketones to be metabolizing fat. The body
does not operate in a binary system where the two
choices are:

(1) Maintain deep ketosis …or…
(2) Become obese

Just because you're not in ketosis doesn't mean
you're somehow not metabolizing fat so that
the only other possible destination for it is to be
stored.6

Ketone esters and salts can be ingested in an attempt to
mimic a ketogenic state and work by elevating blood ketone
levels to force the burning fat as fuel while interfering
with certain other glycogen-related metabolic pathways.
Whether supplements are the equivalent of a ketogenic diet
in terms of benefits has been tested in humans only to a
limited extent. In animal trials, they are not entirely equivalent
and this appears also to be the case in humans. Let's start
first with the animal experiments. The positive finding is
that a 28-day administration of five ketone supplements
on blood glucose, ketones, and lipids in male Sprague–
Dawley rats caused a rapid and sustained elevation of
beta-hydroxybutyrate and a reduction of blood glucose.7 No
doubt, this represented a shift in the energy source to make
use of the ingested ketones.

However, in a comparative trial of a ketogenic diet,
ketone supplementation and control diet examining both
control and chronic stress conditions, results differed
with the intervention. Chronic experiments showed that
under control conditions, only the ketogenic diet resulted in
pronounced metabolic alterations and improved performance
in the novel object recognition test and only the ketogenic diet
prevented stress-induced deficits at the end of the trial and improved certain other aspects of performance. The advantage was to the ketogenic diet rather than supplementation in the
areas of blood glucose, insulin and overall fat metabolism.8
Ketone supplements in animal models do indeed provide
benefits, but not at the level of diet-induced endogenous
production.

Thanks to recently published clinical trials, in the area
of human athletic performance there now is evidence as
to the limitations of ketone supplements. In one study,
ten healthy adult males with similar athletic abilities and
body mass indices fasted and then consumed either beta-hydroxybutyrate
ketone salts or a matched placebo in a
randomized order followed by a cycling time trial. Power
output on the day participants consumed ketone salts was
seven percent lower than on the day they consumed the
placebo. As observed by study co-author Jonathan Little,
assistant professor in University of British Columbia's
(UBC) Okanagan's School of Health and Exercise Sciences,
"Elevated blood ketones seem to inhibit the body's use of
glycogen, the stored form of glucose, and favours burning
fat instead."9,10 A previous study utilizing ketone esters
(573 mg/kg athlete body weight) in conjunction with
carbohydrate consumption had positive findings of better
performance in cycling to exhaustion trials.11

The authors of both studies seem to agree that the
ingestion of ketones leads to nutritional ketosis that alters
the hierarchy of fuel substrate usage during exercise and
it is clear that as the intensity of exercise increases, the
demand for carbohydrate as an energy source increases.
The ketone salt trial tested shorter and higher intensity
training versus the longer period tested in the ketone ester
trial, hence these were not entirely apple-to-apple trials.
In addition, the ketone ester trial tested roughly 30 grams
of ketone ester taken in conjunction with carbohydrate
leading to significant benefit versus carbohydrate alone.
However, bicycle ergometer time trial performance was only
approximately two percent greater using the ketone ester
plus carbohydrate versus carbohydrate alone "representing a
modest increase in physical capacity in these highly trained
athletes, despite significant changes in muscular metabolism."
This finding, once again, indicates the difficulty of fully
substituting ketones for glycogen-dependent aspects of
muscle performance.

The latest studies continue the trend from above.
Ingested ketones, for instance, as esters, impaired
performance in elite cyclists in ˜31 kilometer laboratory-based
time trials on a cycling ergometer programmed to
simulate the 2017 World Road Cycling Championships
course.12 Achieving overall fat / keto adaptation via dietary
means is more successful. Nevertheless, aside from the
difficulty in following such diets, keto adaptation to a low
carbohydrate, high fat diet requires time. Three weeks
clearly is not sufficient even in highly trained athletes such
as elite endurance walkers.13 Ten weeks in trained athletes
appears to be on the margin, improving feelings of wellbeing,
but not performance.14 At least insofar as attested
in published trials, a full 12 weeks or more of adaptation is
required even in the relatively young (20 subjects, 33 ± 11
years) and vigorous to achieve superior endurance results
in comparison to a high carbohydrate diet.15

The above findings lead this author to the observation
that although ketone ester-induced ketosis may increase
metabolic flexibility during exercise by reducing glycolysis
and increasing muscle fat oxidation, the benefits during shorter time periods and/or higher VO2/max
demands are either not great or actually negative. Metabolic
flexibility in the ester trial, such as it was, required the coingestion
of carbohydrate. Without the co-ingestion of
carbohydrate, as demonstrated in the other ketone trials
(both salt and ester), there was a significant inhibition of the
ability to access glycogen stores for energy upon demand.

Metabolic Fitness Supplements

Before looking at individual supplements, it is important

to understand that nutrients that aid metabolic fitness
generally fulfill a number of requirements, among them the
following:

It is helpful to support fat metabolism directly such as through improved transport of fatty acids into the mitochondria for oxidation.

Insulin sensitivity must be improved and maintained and insulin levels kept low.

The release of fatty acids from fat cells likely is less important than is dis-inhibiting fatty acid metabolism. The first is accomplished with caffeine, yet often with a downside such as increased cortisol levels, hence alternatives to caffeine and other similar stimulants are needed.

Inclusion of substances that actively promote fatty acid oxidation is important to help kick-start the body's ability to metabolize fats.

Excessive gluconeogenesis by the liver (creation of glucose from glycogen in response to the release of glucagon) should be inhibited to promote fatty acid oxidation as the alternative.

With diets that are heavy in alcohol and fat, potential "reverse" effects must be prevented.

The sources of useful supplements are not generic and
this should be kept in mind because different production
methods lead to different products with different results.
The following discussion reviews key nutrients that fulfill
one or more of the above requirements.

Potassium-Magnesium Hydroxycitrate
Very few athletes are aware of the benefits of (–)-hydroxycitric
acid (HCA) for sports despite some impressive findings
in terms of greater endurance and faster recovery plus
reduced inflammation. This is because early trials—there
were several large ones—failed to produce benefits for
reasons that, in retrospect, are obvious. First, calcium
HCA and calcium-containing HCA salts exhibit very poor
uptake and poor results in comparative trials.16,17,18 To this
should be added the "food effect," meaning the finding
that consuming food within 30 minutes of ingesting HCA
typically reduces uptake by approximately 60 percent.
HCA salts under normal delivery never exhibit more than
lackluster bioavailability, hence any reduction of that already
modest uptake into the system leads to extremely poor
results. A third factor is that even seemingly nearly identical
HCA salts (as tested by standard high performance liquid
chromatography / HPLC) produced by slightly differing
production techniques can exhibit up to 10-fold differences
in bioavailability.19 Notably lacking in the research literature
is any attempt to determine cellular uptake, an issue separate
from bioavailability. Published research simply assumes that
all uptake issues can be reduced to bioavailability, meaning
blood levels, an assumption proven to be invalid with a
number of nutritional substances, such as coenzyme Q10.

One way around these uptake problems with HCA is by
means of a special liquid delivery. HCA salts normally are
not stable in ready-to-drink formats and break apart to yield
what is known as a lactone. The HCA lactone leads to good
uptake—bioavailability—but little or no benefits because
the molecule exhibits the wrong shape.20 A recently issued
US patent describes a method that not only stabilizes
HCA salts in liquid, but also dramatically improves their
bioavailability and physiologic efficacy.21

Properly produced and delivered HCA can lead to
striking improvements in early fat utilization for energy,
glycogen sparing and increases in endurance. This is in
part because HCA helps to control the muscle's selection
of fuels, an experimental finding from twenty years ago.22
More recently, using mice as the model, HCA ingestion for
13 days was found to increase fat oxidation and improve
endurance exercise time to fatigue by 43 percent compared
to a placebo.23 Chronic HCA ingestion alters fuel selection
rather than the simple release of fat from stores as is true of
lipolysis per se, i.e., the mechanism for HCA is not the same
as with caffeine, capsaicin, etc. Second, the combination of
HCA plus L-carnitine improves glycogen status in liver and
various muscle tissues versus placebo in exercised-trained
rodents. Readers will recall that glycogen-related issues
bulk large in the performance failings of ketogenic diets and
ketone supplements.

What about HCA ingestion in humans? Similar positive
endurance results were found by the same laboratory both
with untrained men and women and with trained athletes as
found in the animal tests. The following trial was conducted
in trained athletes leading to significant improvements in
endurance:

Subjects [n = 6] were administered … HCA or
placebo as a control (CON) for 5 d, after each
time performing cycle ergometer exercise at 60%
VO2max for 60min followed by 80% VO2max until
exhaustion.24

Under the conditions of the trial, time to exhaustion at 80
percent VO2max went from approximately six minutes to
approximately 8.5 minutes, which is a remarkable level of
improvement. Lactate levels were lower. In evaluating the
results, it must be observed that the earlier animal trials
indicated that there is a greater shift in metabolism if the
ingestion period lasts longer. But note clearly: the HCA
salt used in these trials was a pure synthesized trisodium
hydroxycitrate, not the usual HCA available as a dietary
supplement.25

Another benefit from HCA is as much as a 100 percent
improvement in glycogen repletion in muscle after exercise
when a post-workout snack is consumed.26

An issue that almost always is ignored with HCA is that
under conditions of accelerated use of fat for energy, such
as during fasting or ketogenic diets, there is a cycle that
can undermine the compoundfs effects on fat metabolism
by activating inside cells the substance acetyl-CoA
carboxylase.27 Two compounds that help to prevent this
and actually improve fatty acid oxidation are caffeic acid and
mangiferin (a constituent of mango leaf).

Caffeic acid is interesting for a number of reasons.
For current purposes, it has been shown to improve the
ability to metabolize fats for energy and also to promote the
ability of glucose to enter cells, i.e., it is insulin sensitizing.
In terms of HCA, caffeic acid helps block the actions of
acetyl-CoA carboxylase.28 This means that it helps to block
the impact of high alcohol intake and high fat intake or
fasting on HCA, thus allowing HCA to perform the function
of disinhibiting fatty acid metabolism via β-oxidation as
mentioned above.

Mangiferin, the primary active component in mango leaf
extract, is even more significant than is caffeic acid. With
regard to HCA, mangiferin, like caffeic acid, inhibits acetyl-
CoA carboxylase. However, matters do not stop there. In
various in vitro and animal trials, mangiferin increased fatty
acid oxidation. A major finding is that the compound does
the same, and safely, in human beings. Overweight patients
with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L,
and total cholesterol ≥ 5.2 mmol/L) were included in a
double-blind randomized controlled trial. Participants were
randomly allocated to groups, either receiving mangiferin
(150 mg/day) or an identical placebo for 12 weeks. As
reported in the published study,29

A total of 97 participants completed the trial.
Compared with the placebo control, mangiferin
supplementation significantly decreased the
serum levels of triglycerides and FFAs, and insulin
resistance index. Mangiferin supplementation
also significantly increased the serum levels of
mangiferin, high-density lipoprotein cholesterol,
L-carnitine, β-hydroxybutyrate, and acetoacetate,
and increased lipoprotein lipase activity.

The increase in β-hydroxybutyrate and acetoacetate as
well as lipoprotein lipase activity is a clear indication that
mangiferin improves the availability of stored fats and
promotes the oxidation of these fats for the production of
energy as they became available.

Asparagine, Malate and Aspartates for Energy and Endurance

Some of the best supplements for health and sports
have, as it were, slipped under the radar over the years.
We tend to be attracted to whatever is "new" to the point
of overlooking that these new items often are not actually
novel, just older concepts dressed up in new terminology. A
good example of this is the great fanfare given to the recent
"discoveries" involving nicotinamide riboside. (Caloric
Restriction, Fasting and Nicotinamide Riboside TotalHealth
Feb 2015)30 Proffered benefits include anti-aging effects,
better energy metabolism and endurance.31 Strikingly,
both the mechanisms involved and the benefits, upon
closer examination, look remarkably similar to the benefits
associated with what is known as the malate-aspartate
shuttle. The anti-aging benefits, for instance, are similar to
those associated with the Chinese herb rock lotus, which
activates the enzyme (malate dehydrogenase) linked with
this shuttle. (Uncovering the Longevity Secrets of the ROCK
LOTUS TotalHealth April 2010)32

For the hard science minded, the malate/aspartate shuttle
is a principal mechanism for the movement of reducing
equivalents from the cytoplasm to the mitochondria. In
other words, this mechanism keeps energy as electrons
flowing from the cytoplasm of the cell into the mitochondria
and supports the production of adenosine triphosphate
(ATP), the basic energy unit of the body. Ketones can play
a similar role. As expressed in a recent paper, "cellular
energy production depends on the metabolic coenzyme
nicotinamide adenine dinucleotide (NAD), a marker for
mitochondrial and cellular health. Furthermore, NAD
activates downstream signaling pathways (such as the
sirtuin enzymes) associated with major benefits such as
longevity and reduced inflammation... [a ketogenic diet] will
increase the NAD+/NADH ratio."33 (NAD exists in oxidized
and reduced forms, NAD+ and NADH.) This process is
exactly what the recent discoveries regarding nicotinamide
riboside are about. The shuttle also is involved in
replenishing oxaloacetate, which was mentioned above
with regard to ketogenesis and the Krebs/Citric Acid Cycle.
Part of the role of oxaloacetate is shown in the diagram.

Now it just so happens that malic and aspartic
acid (the "salts" are termed malate and aspartate) are
components of this movement of energy. Malate, aspartate
and the compound asparagine are known as oxaloacetate
precursors. Many athletes use citrulline malate to help
promote performance and reduce fatigue thinking that it is
the citrulline that is active although, in fact, it is the malate.
For instance, in an animal trial a month of supplementation
with L-malate increased swimming time endurance by
between 26.1 and 28.5 percent.34 The researchers observed
the activities of cytosolic and mitochondrial malate
dehydrogenase were significantly elevated in the L-malate-treated
group compared with the control group.

As pointed out in the TotalHealth article on the rock
lotus, the malate dehydrogenase enzyme takes a period of
time to be increased in the cell. A number of acute trials of,
for instance, aspartates in athletes, compounds that affect
the same shuttle mechanism, failed, but this should have
been expected due to basic physiology and one wonders
why those researchers even bothered. Under conditions of
moderate exertion, supplementation with asparagine and
aspartate plus L-carnitine increased time to exhaustion by
approximately 40 percent.35 In another animal trial, this
time with intense exercise and only the two amino acids, the supplemented group showed higher exercise
time, lower blood lactate concentration and a decreased the
rate of glycogen degradation compared to control leading
to the conclusion that "supplementation may increase the
contribution of oxidative metabolism in energy production
and delay fatigue during exercise performed above the AT
[anaerobic threshold]."36

To be sure, there are skeptics regarding magnesium—potassium aspartates for use as ergogenic aids.37 However,
the proposed mechanisms of action until recently have been
wrong, the time frame for supplementation (acute rather
than chronic), the amounts supplemented, etc., typically
have been quite wide of the mark. The key mechanism of
action involves the shuttle and oxaloacetate. Interestingly,
this mechanism also promotes the proper metabolism of
that great enemy of athletes, lactic acid. Lactic acid actually
can be converted back into an energy source during exercise.
As Ben Greenfield explains things in a wonderful post,38
A significant rate limiting step of converting
lactic acid into glucose is the conversion of the
molecule Nicotinamide Adenine Dinucleotide
(NAD) into Nicotinamide Adenine Dinucleotide
Hydrogenase (NADH). So what does this have to
do with oxaloacetate? In studies, acute oxaloacetate
exposure enhances resistance to fatigue by
increasing NAD to NADH conversion and allowing
lactic acid to get recycled and converted to glucose
at a much higher rate.39

Oxaloacetate is notoriously unstable and difficult to
supplement orally. A mixture of its precursors (aspartate
salts, asparagine and a malate source) plus an activator
of the malate dehydrogenase enzyme (rock lotus)
supplemented over a period of time (three to four weeks)
is a better way to achieve desired benefits. Finally, another
benefit of a mixture of malate and aspartate is that the
malate-aspartate shuttle plays a role in the regeneration of
L-arginine and the production of nitric oxide.40

Conclusions
Move over, NO (nitric oxide) supplements! Altering muscle
fuel selection and increasing the anaerobic threshold are
the hallmarks of metabolic flexibility in sports. Greater
utilization of stored fatty acids for fuel, reduced lactate
accumulation and better recycling, enhanced glycogen
stores and an elevation of VO2max before the body's
limited stores are called upon without an impairment of
carbohydrate utilization is an ideal situation. It is not clear
that fulfilling this goal demands artificially elevating blood
ketone bodies, either through diet or supplements. Instead,
maximizing the efficiency of energy pathways that make
use of stored fatty acids and the malate-aspartate shuttle
would seem to be not just sufficient, but preferred. Chronic
HCA ingestion alters muscle fuel selection and improves
glycogen stores, especially in conjunction with L-carnitine.
Caffeic acid enhances these actions, as does mangiferin
from mango leaf in ways that have been demonstrated in
humans to augment the metabolism of both fatty acids
and carbohydrates leading to elevated energy production.
The malate-aspartate shuttle and the enzyme malate
dehydrogenase support oxaloacetate recycling and the
efficient operation of the citric acid cycle to sustain fatty
acid oxidation and the reconversion of lactic acid to glucose
for use as fuel by the muscles. Surely a clincher for this
approach is that it promises health and anti-aging benefits,
not just improvements in athletic performance.

Many of us start off the year with a determination—backed by a gym membership—
to get into shape and lose weight. It now is February.
How are those New Year's resolutions faring? Is it time for Plan B?

If that means diets and weight loss aids, there is no one-size-fits-
all. Choosing the right approach with realistic expectations
as to how much can be lost and how quickly will help prevent
frustration and disappointment, not to mention major weight
regain later in the year. Research in advance is the key. The
following are some major categories and rationales for weight
loss supplements:

Appetite suppressants and mood enhancers

Calorie (carbohydrate and/or fat) absorption blockers

Diuretics and laxatives

Metabolism enhancers and thermogenic agents

Nutrient partitioning agents

Of the above approaches, for many reasons, the most commonly
adopted method remains that of metabolism enhancers and
thermogenic agents. Typical ingredients for this tactic for weight
loss are bitter orange, caffeine, country mallow, green tea,
guarana, 7-keto DHEA, synephrine, yerba mate and yohimbe.
Inasmuch as one or more of these ingredients can lead to side
effects if used incorrectly or by individuals for whom they are
inappropriate, the following observations start by examining
thermogenic agents.

How Do Thermogenic Agents Function Within the Body To Burn Fat?
Thermogenesis literally means causing the production of
heat. Aside from the shivering response to cold, body heat
production is a side effect of exercise and or of increased basal
metabolic rate. The thermic effect of food ideally should be on
the order of 10 percent of calories consumed. Thermogenic
products are designed to stimulate the metabolism to be
above where it normally would be in order to burn additional
calories and to access fatty acids for this purpose. The most
common approach for achieving this is to manipulate one of
the body's hormonal signals, usually norepinephrine. Green
tea epigallocatechin gallate (EGCG) reduces norepinephrine
degradation and thereby increases catecholamine-mediated
stimulation of β-adrenergic receptors and activates the
sympathetic side of the nervous system. Ingesting EGCG by
itself and in conjunction with caffeine prolongs the actions
of norepinephrine. This increases the metabolic rate, hence
increases energy expenditure by increasing the oxidation of
glucose and fat for energy and increasing calorie-consuming
actions. As a rule, there is a significantly greater mobilization
and utilization of fat for energy than glucose—in fact, most
metabolic stimulants cause fat to be released from storage
so that it is more readily available for energy generation. The
stimulation involved may make a person more wide awake and
even more inclined to exercise, but some of the stimulation may
involve what are termed "futile cycles" that consume energy
and create heat, but do not lead to physical exertion.

How Can Those Who Want To Avoid the Negative Effects of Stimulants Benefit From Thermogenic Agents?
There are at least three side effects that dieters should look to
avoid: 1) increased heart rate, 2) increased blood pressure and
3) excessive central nervous system stimulation. One solution
to the cardiovascular side of things is to improve the circulation,
especially to the heart. Hawthorne extracts help to open the
circulation of the coronary artery, that is, the main blood supply
to the heart. Herbs such as specialized grape seed extract and
wild bitter melon, similarly, are useful for supporting the body in
blood pressure regulation. The mineral magnesium is another
aid here in that it both helps to regulate blood pressure and is
calming to the nervous system.

Excessive stimulation that overly activates the central
nervous system leading to agitation, emotional control issues
and/or sleeplessness actually does not usually increase
thermogenesis, a fact that emerged from the ephedra-caffeine
trials at Harvard and elsewhere. The clearly thermogenic
combination of ephedra-caffeine increased energy expenditure
at low to moderate doses, but above a not particularly high level
of intake the amount of extra calories burned went down rather
than up. Moreover, excessive stimulation induces a release of
cortisol, which tends to cause the loss of lean tissue rather than
fat tissue.

For Consumers Who Use Caffeine To Increase Their Metabolism,
What Are the Concerns Surrounding Caffeine?

Caffeine definitely is a mixed bag when it comes to metabolism.

Looking only at caffeine by itself, there is evidence for acute increases in resting metabolic rate and thermogenesis, but habituation nullifies such benefits with chronic intake.

Habitual caffeine use reduces the benefits of caffeine/EGCG mixtures compared to findings in test subjects who do not consume significant amounts of caffeine regularly.

Overall, there is little or no support for the claim that caffeine by itself induces or maintains weight loss over the long term.

In short, caffeine is more useful for metabolic effect if
consumed with something like EGCG, such as from green tea,
but habituation is rapid. Caffeine-related compounds in green
mate appear to have more benefits over the long term than does simple caffeine. The health benefits of coffee, such as they
are, come from chlorogenic acid and related compounds, not
mainly from the caffeine.

Keep in mind, an intake of 700 mg or more caffeine per day
(about five cups of coffee) is often associated with depression
and mood swings. Some authorities draw the line at 600 mg
per day. Caffeine causes short-term increases in blood sugar
levels that can be followed by dramatic downward fluctuations.
Consuming caffeine, in other words, is yet another path to
the sugar "roller-coaster" of energy ups and downs and sugar
cravings. Cutting out caffeine and refined sugars for as little as
one week has been shown clinically to improve mood in many
individuals complaining of depression.1

What Are Some of the Concerns Surrounding Weight Loss Supplements, Such as Synephrine and Yohimbe?
No doubt, the major concerns are elevated blood pressure and
elevated heart rate. In addressing these concerns, the source of
synephrine is important. ρ-synephrine is an alkaloid occurring
naturally in some plants and animals. A related compound is
found in approved drugs as the m-substituted analog known as
neo-synephrine. Bitter orange (Citrus aurantium) is a source of
ρ-synephrine, which does not seem to increase blood pressure
significantly, although it may have an effect on heart rate. (http://www.medsci.org/v09p0527.htm) m-Synephrine, often confused in the literature with ρ-synephrine, exhibits cardiovascular
effects, but reportedly is not a constituent of bitter orange. It
remains controversial whether ρ-synephrine exerts effects on
blood pressure and heart rate if consumed with large amounts
of caffeine or other stimulants.

ρ-Synephrine is used to increase energy expenditure and
lipolysis; ρ-synephrine is a β-3 adrenergic receptor agonist,
which is to say, a thermogenic compound. By itself, ρ-synephrine
as found in bitter orange is not associated with significantly
increased blood pressure or heart rate; no significant
α-adrenergic effects have been demonstrated, unlike the case
with, say, ephedrine.2 Again, synthetic synephrine is a slightly
different compound and can lead to high blood pressure and
other effects even at relatively modest doses.

It is neither necessary nor useful to push an intake of
ρ-synephrine above approximately 50 mg. Rather, greater energy
expenditure is induced by adding 600 mg naringenin to the
mixture and a further increase can be induced by adding 100 mg
hesperidin. (https://www.ncbi.nlm.nih.gov/pubmed/21537493)

Another widely promoted thermogenic herb is yohimbe
(Pausinystalia yohimbe). It is claimed as a thermogenic agent due
to its active component, yohimbine, an α-2 receptor antagonist.
Three double-blind RCTs, which included patients who were
> 15–20 percent over their ideal body weight or had a BMI
ranging between 28 and 48 and lasted three weeks to six
months, yielded weight loss only at three weeks on a restricted
diet, the loss being 1.34 kg greater than with placebo.3 However,
yohimbe exhibits erratic effects on blood pressure, heart rate
and neurological parameters with a high risk of toxicity.4

How Do the Satiety Supplements 5-HTP and Hydroxycitric Acid Work?
Items that affect serotonin, such as 5-HTP
(5-hydroxytryptophan) and St. John's Wort, may influence
mostly carbohydrate consumption. 5-HTP activates
serotogenic pathways and at 600 to 900 mg/day induces
weight loss of 3.1–3.7 pounds in 5–6 weeks without dieting.
At 900 mg, 70 percent of subjects experienced significant
nausea, but adjusted after six weeks.5 Although anyone being
treated with pharmaceutical psychoactive drugs should not use
5-HTP without their doctor's agreement, 5-HTP otherwise has
been found to be safe at ordinary dosages.6

(–)-Hydroxycitric Acid / HCA, always sold as a mineral salt,
is unusually well studied with at least 12 randomized placebo-controlled
trials, but studies have used different salts and widely
differing dosages. Mechanisms of action remain controversial.
HCA does not cross the blood-brain barrier, hence does not
influence the central nervous system directly; neither does it
depend on activating nerves involving the liver (vagal afferents).
HCA delays gastric emptying, however, and it prolongs glucose
absorption from the small intestine. The primary effects seem
to be to reduce between-meal snacking and to increase the
length of time that dieters feel satiated after meals. Potassium
and potassium-magnesium HCA salts are insulin sensitizing
at human acceptable dosages whereas calcium- and calcium-potassium
HCA salts are not. Apparently no one has tested the socalled
"triple" salts even in animals. Weight loss in randomized
controlled trials (RCTs) ranges from none to approximately 1/2
to one pound per week for eight weeks at higher dosages (2.8 g
HCA) of potassium-based salts. In other words, approximately
4.5 grams/day of a potassium-based salt can lead to as much
as one pound per week weight loss if taken as directed. Weight
loss normally starts after the first or second week of usage for
reasons having to do with refilling glycogen stores in the liver
and muscle as well as greater hydration of muscle tissue. No
toxicity or significant side effects have been found with properly
manufactured HCA salts in controlled trials and safety reviews.
Despite extremely widespread usage for roughly 25 years, only
a handful of adverse event reports have appeared, usually with
combination products and/or in cases in which the report could
not even name the HCA salt involved.7,8

Do Chia Seeds and Similar Foods Promote Satiety?
Good fiber sources, especially very viscous fibers, increase
satiety by increasing stomach distention (the feeling that
the stomach is extended and full) and reducing the rate of
gastric emptying. They also tend to reduce the rate at which
carbohydrates release glucose into the blood stream. Viscous
soluble fibers include, but are not limited to pectins, β-glucans,
psyllium, glucomannan and guar gum. Foods such as ground
flax seed, baked acorn squash, artichoke hearts and most
legumes are good fiber sources. Oats and barley are good
items, but not if they have been "instantized" since this process
causes them to act more like high-glycemic foods.

Protein sources also are good for satiety, although one can over-consume calories from protein just like anything else.
Plant protein sources are slower to be absorbed into the tissues
and thus may be especially good for prolonging satiety.
At the other end of the scale, fructose is a particularly
bad sugar for dieters and for health in general. Indeed, it is
significantly worse than glucose or sucrose according to recent
research.

How Do Fat and Carbohydrate Blockers Aid in Weight Management?
White kidney bean extracts and a number of other products,
including bitter melon, inhibit carbohydrate digestion by
inhibiting the actions of alpha-amylase and/or related
compounds. The drawback of these in the American diet is that
more and more calories in our diet are from corn sugar and
other simple sugars. Indeed, corn sugars often are the cheapest
binders and fillers available for processed foods. Carb blockers
may be helpful with traditional foodstuffs, but this is modern
America. Corn is subsidized and processed corn components
are everywhere.

HCA reduces the rate at which carbohydrates are available,
but it is not a traditional carbohydrate blocker. Its mechanism
of action is different in that it slows and prolongs the passage of
glucose across the gut membrane into the blood stream via its
effects on the sodium pump in the gut. There likely are a small
number of other supplements that work similarly.

A well-known lipase inhibitor (blocker of fat digestion) is
derived from Cassia Nomame Mimosoides. This item was created
to mimic the actions of a pharmaceutical weight loss product
that inhibits the absorption of 30 percent of fat found in the
diet. Concerns are sometimes expressed as to the wisdom on
preventing the proper digestion of fats in the small intestine.
Unlike carbohydrates, which can be acted upon by various
bacteria in the large intestine, the body is poorly equipped to
chronically handle fats not digested in the normal fashion. At
this point in time, even the pharmaceutical fat blockers have
largely disappeared and no trials seem ever to have been
undertaken to demonstrate the efficacy of "natural" fat blockers
claimed to be natural alternatives to the drugs.

Begin with Your Eating and Exercise Habits
To repeat a point made in articles in the past, diets that are
inadequate in terms of vitamins and minerals, and in many
cases protein, often coincide not only with weight gain, but
also with low energy levels and mood swings. The consumption
of a diet based largely upon sugars, refined carbohydrates,
soft drinks and "junk foods" in general is just not sufficient to
maintain good bodily health. If the overall quality of health is
poor, it is unlikely that mental functioning and emotional well-being
will fare any better. A powerful incentive for binge eating
and a source of sugar cravings is the effort to counter depression
and mood swings.

Remember, as well, the place of exercise. Exercise is less
important for its role in directly burning calories than for
increasing basal metabolic rate in the morning and helping
the body to access fats for energy. As little as 20 to 30 minutes
walking every day can help the body to relearn how to burn
fat for fuel. Walking early in the day has the added benefit of
speeding up the metabolism when this can do the most good
and also providing a daily dose of mood-brightening sunshine.
Before or after the evening meal are two other good times to
take a walk.

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